August 05, 2014

Can Hypothalamic Inflammation and Leptin Resistance be Reversed?

A new study by yours truly begins to address the key question: can hypothalamic inflammation and leptin resistance be reversed?

Leptin is the primary hormonal regulator of body fatness in the human body (1). Secreted by fat tissue, it acts in many places in the body, but its most important effects on body weight occur via the brain, and particularly a brain region called the hypothalamus. The hypothalamus is responsible for keeping certain physiological variables within the optimal range, including blood pressure, body temperature, and body fatness.

In obesity, the brain loses its sensitivity to leptin, and this causes the body to begin 'defending' a higher level of body fatness, analogous to how a person with a fever 'defends' a higher body temperature (1). Once a person has become obese, it's difficult to return to true leanness because this system vigorously opposes major fat loss. Leptin resistance makes fat loss more difficult.

In rodent models, leptin resistance is caused at least in part by inflammatory signaling in the hypothalamus. We can observe this in multiple ways, but one common way is to look at the appearance of specific cells in the brain that change number, size, and shape when inflammation is present (2). These cells are called microglia and astrocytes. In addition to the work in rodents, we've published preliminary evidence that these same inflammatory changes occur in the hypothalamus of obese humans (2).

A key question is whether or not these inflammatory changes can be reversed. Is a person with leptin resistance doomed to have it forever, undermining fat loss efforts for the rest of his or her life? Or can it be corrected, possibly allowing easier and more sustainable fat loss? We just published a study in Endocrinology that begins to answer this question, using a mouse model of dietary obesity (3). I'm co-first author of this study along with my colleague Kathryn Berkseth, MD. My former mentor Mike Schwartz, MD is senior author.